[go: up one dir, main page]

US4211794A - N,N-Disubstituted aminomethylphenylethanolamines - Google Patents

N,N-Disubstituted aminomethylphenylethanolamines Download PDF

Info

Publication number
US4211794A
US4211794A US06/001,989 US198979A US4211794A US 4211794 A US4211794 A US 4211794A US 198979 A US198979 A US 198979A US 4211794 A US4211794 A US 4211794A
Authority
US
United States
Prior art keywords
aminomethylphenylethanolamine
disubstituted
meta
interferon
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/001,989
Other languages
English (en)
Inventor
Allen R. Kraska
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp SRL
Original Assignee
Pfizer Corp SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Corp SRL filed Critical Pfizer Corp SRL
Priority to US06/001,989 priority Critical patent/US4211794A/en
Priority to DE8080300012T priority patent/DE3061280D1/de
Priority to EP80300012A priority patent/EP0013592B1/en
Priority to GR60895A priority patent/GR73604B/el
Priority to IE19/80A priority patent/IE49242B1/en
Priority to JP55000474A priority patent/JPS5934175B2/ja
Priority to DK005880AA priority patent/DK154421B/da
Priority to DK5880A priority patent/DK5880A/da
Application granted granted Critical
Publication of US4211794A publication Critical patent/US4211794A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • antiviral compounds which attack mammals, including man, are normally contagious afflictions which are capable of causing great human suffering and economic loss.
  • antibacterial and antifungal agents This is due in part, to the close structural similarity of viruses and the structure of certain essential cellular components such as ribonucleic and deoxyribonucleic acids.
  • numerous non-viral "antiviral agents” i.e. substances "which can produce either a protective or therapeutic effect to the clear detectable advantage of the virus infected host, or any material that can significantly enhance antibody formation, improve antibody activity, improve non-specific resistance, speed convalescence or depress symptoms" [Herrman et al., Proc. Soc.
  • antiviral agents include, to name a few, interferon and synthetic materials such as amantadine hydrochloride, pyrimidines, biguanides, guanidine, pteridines and methisazone. Because of the rather narrow range of viral infections that can be treated by each of the antiviral agents commercially available at the present time, new synthetic antiviral agents are always welcomed as potentially valuable additions to medical technology.
  • the cells of mammals produce, in response to virus infection, a substance which enables cells to resist the multiplication of a variety of viruses.
  • the viral-resisting or viral-interfering substances are referred to as "interferons".
  • the interferons are glycoproteins which may differ in their physico-chemical properties, but all exhibit the same biological properties; namely they inhibit a wide range of unrelated viruses, have no toxic or other deleterious effects on cells, and are species-specific (Lockart, Frontiers of Biology, Vol. 2, "Interferons", edited by Finter, W. B. Saunders Co., Philadelphia, 1966, pages 19-20).
  • interferon No practical, economical method has yet been developed for the preparation of exogenous interferon for routine clinical use against viral infections.
  • An alternative approach to producing interferon has, therefore, been pursued, which comprises administering a non-viral substance which stimulates or induces production of interferon in the cells.
  • the interferon produced in this fashion is referred to as "endogenous" interferon.
  • polyamines are known to stimulate interferon production and hence have antiviral activity. They include the polyamines disclosed in U.S. Pat. No. 3,872,171, the xylenediamines disclosed in U.S. Pat. No. 4,034,040, and the phenethanolamine substituted, glycerin-based lipids disclosed in Ser. No. 825,535 allowed Feb. 12, 1979, now U.S. Pat. No. 4,166,132. Other related phenthanolamine substituted, glycerin-based lipids not having antiviral activity are disclosed in Ser. No. 906,260 allowed Feb. 12, 1979, now U.S. Pat. No. 4,173,641.
  • an N,N-disubstituted aminomethylphenylethanolamine or its pharmacologically acceptable mineral acid or organic acid salt is capable of combatting viral infections in mammals by stimulating or inducing the production of endogenous interferon.
  • the structural formula of the aminomethylphenylethanolamine is: ##STR1## wherein R 1 is hydrogen or alkyl having from 1 to 4 carbon atoms, R 2 and R 3 are the same or different and each is n-alkyl of from 12 to 20 carbon atoms and the benzene ring is meta or para-disubstituted.
  • a preferred embodiment of the invention is the aminomethylphenylethanolamine wherein R 2 and R 3 are the same. This type of amine group substitution facilitates synthesis as a result of the commercial availability of the corresponding starting material amine, R 2 R 3 NH.
  • Other preferred embodiments of the invention are the two aminomethylphenylethanolamines wherein R 2 and R 3 are each n-tetradecyl and wherein R 2 and R 3 are each n-hexadecyl. These substitutions tend to optimize the anti-viral activity.
  • Especially preferred embodiments of the invention include the aminomethylphenylethanolamine wherein R 1 is hydrogen, the benzene ring is meta-disubstituted and R 2 and R 3 are each n-hexadecyl; the aminomethylphenylethanolamine wherein R 1 is ethyl, the benzene ring is meta-disubstituted and R 2 and R 3 are each n-hexadecyl; the aminomethylphenylethanolamine wherein R 1 is isopropyl, the benzene ring is meta-disubstituted and R 2 and R 3 are each n-hexadecyl; and the aminomethylphenylethanolamine wherein R 1 is t-butyl, the benzene ring is meta-disubstituted and R 2 and R 3 are each n-hexadecyl.
  • Their biological activities in the antiviral and other tests described infra make them outstanding examples of the present invention.
  • the invention also includes a pharmaceutical formulation of an N,N-disubstituted aminomethylphenylethanolamine of the invention or its pharmacologically acceptable salt and methods of treating a viral infection and inducing the production of interferon using such an aminomethylphenylethanolamine or salt.
  • the pharmaceutical formulation is useful for the treatment of an interferon sensitive viral infection in a mammal and comprises an antivirally effective amount of an aminomethylphenylethanolamine or its salt and a pharmaceutically acceptable carrier.
  • the method of prophylactically controlling an interferon sensitive viral infection in a mammal comprises administering to the host an antivirally effective amount of an aminomethylphenylethanolamine or its salt and the method of inducing the production of interferon in a mammal comprises administering an effective amount of an aminomethylphenylethanolamine or its salt.
  • an aminomethylphenylethanolamine of formula I is prepared, as illustrated in Scheme A, infra, by an amination reaction of an epoxide of formula II using an amine of formula R 1 NH 2 .
  • the amination reaction procedure follows methods well known in the art and any may be employed with success.
  • the reaction may be conducted neat, in an excess of R 1 NH 2 at a temperature range of from about 30° to 130° under sealed vessel conditions until the reaction is substantially complete.
  • the reaction may be conducted in a polar, protic or aprotic solvent at a temperature from about 30° to reflux until the reaction is substantially complete.
  • Useful polar solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, chloroform, methanol, ethanol and the like.
  • a polar, protic solvent it is advantageous to use an excess of the amine R 1 NH 2 . Under any procedure, a stoichiometric ratio of epoxide to amine should be used and an excess of the amine will usually provide a favorable yield.
  • Reaction (1) An alpha halo meta or para tolunitrile of formula III is reacted with a disubstituted amine of formula HNR 2 R 3 is polar, aprotic solvent while optionally using a suitable hydrogen halide neutralizing agent, to form an N,N-disubstituted aminomethylbenzonitrile of formula IV.
  • Appropriate reducing agents include hydrogen and nickel catalyst using hydrazine followed by aqueous sulfuric acid; nickel-aluminum amalgam, formic acid and water; lithium triethoxyaluminum hydride; sodium triethoxyaluminum hydride; stannous chloride and hydrogen chloride followed by water; and diisobutylaluminum hydride.
  • a preferred reducing agent is diisobutyl aluminum hydride. Use of these reducing agents is well known in the art. Reduction by any of these methods will produce in situ the intermediate Schiff base which is then hydrolyzed to the benzaldehyde of formula V by water present in the reaction mixture or by addition of water to the reaction after reduction is complete.
  • the epoxide of formula II is prepared from the benzaldehyde of formula V by reaction with the sulfur ylide, dimethyloxosulfonium methylide, or other appropriate sulfur ylide in a suitable solvent such as ether, tetrahydrofuran, glyme, diglyme, dioxane and the like. This method is well-known in the art.
  • N,N-disubstituted aminomethylphenylethanolamines of the invention may also be synthesized using other routes and techniques that are thoroughly familiar to those skilled in the art.
  • Suitable mineral acids appropriate for the salt formation include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid and the like.
  • Suitable organic acids appropriate for salt formation include, but are not limited to, tartaric, citric, glycolic, propionic, butyric, succinic, maleic, gluconic, lauric, malonic, fumaric, stearic, lactic, palmoic, isobutyric, benzoic, and tosic acids and the like.
  • novel aminomethylphenylethanolamines of this invention and the pharmacologically acceptable salts thereof are effective in treating viral infections by stimulating or inducing the production of endogenous interferon and in stimulating cellular mediated immune response.
  • Examples 5, 6 and 7 illustrate the achievement of these effects and are standard biological tests to determine (a) prophylatic ability to protect against encephalomyocarditis (EMC) virus, (b) ability to promote rejection of Sarcoma 180J tumor cells and (c) ability to non-specifically stimulate peritoneal macrophages.
  • EMC encephalomyocarditis
  • novel aminomethylphenylethanolamines of this invention can be used in a variety of pharmaceutical formulations which contain the compound or a pharmacologically acceptable salt thereof, and may be administered by a variety of conventional routes, such as intravenous, intramuscular, subcutaneous, intranasal, topical and intraperitoneal.
  • the aminomethylphenylethanolamines or their pharmacologically acceptable salts may be administered alone or in combination as a pharmaceutical formulation using pharmaceutically acceptable carrier material such as inert solid diluents, aqueous solutions or various non-toxic, organic solvents in dosage forms such as gelatin capsules, tablets, powders, lozenges, syrups, injectable solutions and the like.
  • pharmaceutically acceptable carrier material such as inert solid diluents, aqueous solutions or various non-toxic, organic solvents in dosage forms such as gelatin capsules, tablets, powders, lozenges, syrups, injectable solutions and the like.
  • Such formulation material may include water, ethanol, gelatins, lactose, starches, vegetable oils, petroleum jelly, gums, glycols, talc, benzyl alcohols and other known carriers for medicaments.
  • these pharmaceutical formulations may also contain auxillary material such as preserving agents, wetting agents, stabilizing agents, lubricating agents, absorption agents, buffering agents and iso
  • administration before exposure to an infectious virus will provide rapid resistance to the virus.
  • administration should take place from about two days to about one day before exposure to the virus, although this will vary somewhat with the particular patient and the particular infectious virus.
  • the aminomethylphenylethanolamines of this invention may be administered by any of the routes mentioned supra in the appropriate pharmaceutical formulation containing a dose of about 1 mg./kg. to about 250 mg./kg. of aminomethylphenylethanolamine with about 1 to 4 doses per day being employed.
  • the preferred range of the dose of aminomethylphenylethanolamine to be used is about 5 mg./kg. to about 50 mg./kg.
  • Administration of a pharmacologically acceptable salt of the invention will follow the same procedure with a corresponding adjustment of the dose given.
  • suitable pharmaceutical formulations containing small doses of the aminomethylphenylethanolamines of this invention will be administered initially and may be increased gradually to determine the optimum dosage for the particular patient. His or her immune competence will generally be monitored following administration, using conventional techniques employed in the art, such as the macrophage activation assay described hereinafter. Typically, maximum activation will be observed about 24 to 48 hours after the initial administration and, absent administration of further doses, will decline to the initial level over a further 24 to 48 hour period. Thus, administration of a second dose approximately 24 to 72 hours after the initial administration will maintain the desired level of immune competence. Generally, 2 to 4 doses will be administered in this manner and the response to treatment of the patient determined. Further doses may then be administered if necessary, as described above. Administration of a pharmacologically acceptable salt of the invention will follow the same procedure.
  • ⁇ -Bromo-m-tolunitrile (1-III) (3.9 g, 0.02 mol), di-n-hexadecylamine (9.3 g, 0.02 mol), and potassium carbonate (27.6 g 0.2mol) were combined in dimethylacetamide (93 ml) and heated (80°-90°; 1.5 hr). The mixture was then poured over ice, stirred cold (15 min), and filtered. The resulting solids were washed with water, dissolved in hexane (70 ml), and filtered. The hexane solution of product was dried over sodium sulfate, filtered and concentrated to an oil under reduced pressure.
  • the desired amine 1-I was converted to the hydrochloride salt by passing hydrogen chloride through a solution of it in ethyl acetate followed by recrystallization from the same solvent (0.4 g, 10% yield): mp 89°-90° C. (HCl salt); NMR (CDCl 3 ) ⁇ 1.48 (t, 3H).
  • Examples 1-4 demonstrate that the other N,N-disubstituted aminomethylphenylethanolamines of the invention can be prepared by substituting the appropriate amine HNR 2 R 3 for di-n-hexadecylamine of the Example 1 conversion step (1-III) to (1-IV) and by substituting the appropriate amine R 1 NH 2 for ethyl amine of the Example 1 conversion step (1-II) to (1-I) or by forming the primary amine according to the procedure of Example 4.
  • Antiviral activity is expressed as the average relative survival (Sr) of 2 runs of experimental groups compared to the controls on the tenth day after challenge.
  • X i number of survivors on the ith day in experimental group
  • e i number of survivors on the ith day in control group.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/001,989 1979-01-08 1979-01-08 N,N-Disubstituted aminomethylphenylethanolamines Expired - Lifetime US4211794A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US06/001,989 US4211794A (en) 1979-01-08 1979-01-08 N,N-Disubstituted aminomethylphenylethanolamines
DE8080300012T DE3061280D1 (en) 1979-01-08 1980-01-03 N,n-disubstituted-aminomethyl-phenylethanolamines and pharmaceutical formulations thereof
EP80300012A EP0013592B1 (en) 1979-01-08 1980-01-03 N,n-disubstituted-aminomethyl-phenylethanolamines and pharmaceutical formulations thereof
GR60895A GR73604B (da) 1979-01-08 1980-01-04
IE19/80A IE49242B1 (en) 1979-01-08 1980-01-07 N,n-disubstituted-aminomethyl-phenylethanolamines and pharmaceutical formulations thereof
JP55000474A JPS5934175B2 (ja) 1979-01-08 1980-01-07 Ｎ，ｎ−ジ置換アミノメチルフェニルエタノ−ルアミン類
DK005880AA DK154421B (da) 1979-01-08 1980-01-07 Analogifremgangsmaade til fremstilling af n,n-di(n-alkyl)aminomethylphenylethanolaminer eller syreadditionssalte deraf
DK5880A DK5880A (da) 1979-01-08 1980-01-07 Analogifremgangsmaade til fremstilling af n,n-di (n-alkyl) aminomethylphenylethanolaminer eller syreadditionssalte deraf

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/001,989 US4211794A (en) 1979-01-08 1979-01-08 N,N-Disubstituted aminomethylphenylethanolamines

Publications (1)

Publication Number Publication Date
US4211794A true US4211794A (en) 1980-07-08

Family

ID=21698725

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/001,989 Expired - Lifetime US4211794A (en) 1979-01-08 1979-01-08 N,N-Disubstituted aminomethylphenylethanolamines

Country Status (7)

Country Link
US (1) US4211794A (da)
EP (1) EP0013592B1 (da)
JP (1) JPS5934175B2 (da)
DE (1) DE3061280D1 (da)
DK (2) DK5880A (da)
GR (1) GR73604B (da)
IE (1) IE49242B1 (da)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4754047A (en) * 1979-08-16 1988-06-28 American Cyanamid Company Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby
US5719193A (en) * 1989-05-23 1998-02-17 Merrell Pharmaceuticals, Inc. Method of potentiating cell-mediated immunity utilizing polyamine derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3927049A1 (de) * 1989-08-16 1991-02-21 Sandoz Ag Halogenalkyl-phenyl-ketone und deren hydrate, ihre herstellung und verwendung

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS505342A (da) * 1973-05-25 1975-01-21
US3872171A (en) * 1971-05-24 1975-03-18 Pfizer Polyamines as antiviral agents in animals
JPS5036434A (da) * 1973-08-08 1975-04-05
US4034040A (en) * 1971-05-24 1977-07-05 Pfizer Inc. Xylene-diamines as antiviral agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3872171A (en) * 1971-05-24 1975-03-18 Pfizer Polyamines as antiviral agents in animals
US4034040A (en) * 1971-05-24 1977-07-05 Pfizer Inc. Xylene-diamines as antiviral agents
JPS505342A (da) * 1973-05-25 1975-01-21
JPS5036434A (da) * 1973-08-08 1975-04-05

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Sill et al., J. Med. Chem., 17, p. 965 (1974). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4754047A (en) * 1979-08-16 1988-06-28 American Cyanamid Company Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby
US5719193A (en) * 1989-05-23 1998-02-17 Merrell Pharmaceuticals, Inc. Method of potentiating cell-mediated immunity utilizing polyamine derivatives

Also Published As

Publication number Publication date
DE3061280D1 (en) 1983-01-20
DK5880A (da) 1980-07-09
IE800019L (en) 1980-07-08
EP0013592A1 (en) 1980-07-23
IE49242B1 (en) 1985-09-04
DK154421B (da) 1988-11-14
GR73604B (da) 1984-03-26
JPS5934175B2 (ja) 1984-08-21
EP0013592B1 (en) 1982-12-15
JPS5594341A (en) 1980-07-17

Similar Documents

Publication Publication Date Title
US4315007A (en) 4-Amino-6,7-dimethoxyquinazol-2-yl alkylenediamines
JP2637737B2 (ja) 新規な薬剤
JPH078851B2 (ja) ３−フエニルチオメチルスチレン誘導体
EP0272478B1 (en) Glycyrrhetic acid derivatives and use thereof
US4211794A (en) N,N-Disubstituted aminomethylphenylethanolamines
US4010202A (en) 5,6-Dihydroxy aminotetralol compounds
HU199502B (en) Process for producing new purine derivatives and pharmaceutical compositions comprising same
JPH032116A (ja) ベンゼン誘導体、その調製およびこれを含有する薬学的組成物
US3182061A (en) 5-[4-(p-hydroxyphenoxy)phenyl]-5-oxo-3-methylvaleric acid
US4451473A (en) 3,7-Diazabicyclo [3.3.1] nonanes having anti-arrhythmic activity
US2483381A (en) Beta-dihydro-inylamine and the acid addition salts thereof
US3211792A (en) 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof
US4788209A (en) Antifungal 2-anilinothiazolines
US3860652A (en) 8-Aminoalkyl substituted dibenzobicyclo {8 3.2.1{9 {0 octadienes
US3150148A (en) 1, 3, 5-trisubstituted pyrazoles
US3718678A (en) 1-({60 -cyanomethylene-hydrazino)-phenoxy-3-aminopropan-2-ols
US4857529A (en) Interferon inducing, anti-vaccinia, and/or anti-influenza compositions
US4514573A (en) Isoprenylamine derivatives
US3228976A (en) 1, 4-bis-(aminomethyl)-1-cyclohexene compounds
Tatsuno et al. Synthesis and adrenergic. beta.-blocking activity of some 1, 3-benzodioxole derivatives
US4745118A (en) Substituted quinazoline-3-oxides providing pharmacological activity
US4104402A (en) 5,6-Dihydroxy aminotetralol compounds
US4593033A (en) Substituted indeno[2,1-c] pyridines useful as calcium channel blockers
US3341591A (en) 1-(o-chlorophenyl)-and 1-(o, p-dichlorophenyl)-2-hydrazinopropanes
US4139711A (en) Dihydroethanoanthracene derivatives